Project Summary Cachexia is a complex syndrome characterized by involuntary weight loss and skeletal muscle wasting that leads to fatigue, weakness and a loss of appetite that is not reversed by increased caloric consumption. More than half of all cancer patients develop cachexia and it is responsible for more than 20% of all cancer deaths. Numerous complications associated with cachexia include an impaired response to drug treatment, an increased chance of infection, a poor prognosis and a decreased quality of life. Currently, there are no FDA- approved treatments for cancer cachexia, but the hormone ghrelin has recently emerged as a molecule with great potential. Several studies in both animals and humans have shown that ghrelin increases food intake, stimulates the release of growth hormone, increases muscle mass, and reduces markers of inflammation. However, the use of ghrelin as a treatment is limited for several reasons: 1) ghrelin must be dosed 2-3 times daily to see efficacy due to its inherently short half-life of 30 min; 2) deacylation of ghrelin to an inactive form occurs in less than 5 min; and 3) ghrelin is currently dosed intravenously to see a therapeutic effect. The studies completed during SBIR Phase I address each of these issues, resulting a long-acting ghrelin derivative that could be dosed subcutaneously once every other day in rats to reverse the effects of cachexia in the Yoshida rat model. The studies proposed in this Phase II application will investigate the ability of our long- acting ghrelin to ameliorate cachexia in two additional models. Methods for cGMP production of the long-acting ghrelin will be put in place. We will perform IND-enabling GLP toxicity and immunogenicity studies using the cGMP material. These studies are needed prior to beginning human trials. Once fully developed, this long- acting ghrelin derivative would provide a patient-friendly cachexia therapy that would significantly improve the prognosis and quality of life in patients with cancer and also in patients with other chronic disorders such as congestive heart failure (CHF) and chronic obstructive pulmonary disease (COPD).